HIV-associated wasting is an important problem in the United States and internationally. Current therapies are often ineffective, for uncertain reasons, in addition to being costly. In order to understand the pathophysiology of HIV-associated wasting and develop a rational basis for therapeutics, we have studied appetite and metabolism, focusing on the role of cytokines. A number of stable isotopic techniques for studying intracellular biosynthesis and intermediary metabolism in humans were developed in our laboratory over the past few years, including the mass isotopomer distribution analysis (MIDA) technique. We have found that HIV infection is associated with several striking metabolic abnormalities. There exists a characteristic metabolic profile at different stages of HIV disease, including asymptomatic seropositivity. Many of these abnormalities have been reproduced y recombinant cytokine administration in animal models. The key clinical questions remain unanswered, however. Our aims are (1) to understand why nutritionally depleted HIV-infected subjects often fail to respond to intravenous nutrition (IVN) or increased oral intake. (2) To develop predictive tests using metabolic parameters for who will respond to feeding and who will not. (3) To test alternative anabolic approaches (growth factors) and characterize how they work. (4) To establish whether metabolic abnormalities are due to cytokines and, if so, whether they prognosticate clinical response to anti-viral therapies. (5) To ask whether metabolic abnormalities are useful as markers of disease activity or immune response, and whether HIV infection per se' is responsible. (6) To compare HIV-infected women to men. These questions will be addressed y combining state-of-the-art metabolic and nutritional measurements with prospective clinical trials (including several ongoing studies) of 4 types: feeding, cytokines/anticytokines, growth factors and anti-virals. The influence of metabolic abnormalities on response to IVN and dronabinol will be determined. The role of cytokines will be evaluated by the metabolic and nutritional effects of anti-cytokine interventions (pentoxyfilline, n-3 fatty acids), of interleukin-2 in humans and of recombinant cytokines in rats. We will compare the metabolic and nutritional actions of recombinant insulin-like growth factor-1 and growth hormone. The effect of early AZT treatment and other anti-virals on metabolism and, conversely, the influence of metabolic abnormalities (as indices of cytokine presence) on antiviral responsivity will also be addressed. Finally, we will try to extend the MIDA technique to new biosynthetic pathways, including in vivo viral replication and muscle protein synthesis. In summary, we propose to build on recent methodologic advances to understand the nutritional and general clinical implications of altered metabolism in HIV disease, with a particular emphasis on the problem of nutrient-unresponsive wasting and the role of cytokines.